Chemokines are a class of cytokine molecules that are involved in cell recruitment and activation in inflammation. These chemokines have been classified into four subgroups, depending on the nature of the spacing of two highly-conserved cysteine amino acids that are located near the amino terminus of the polypeptide. The first chemokine subgroup is referred to as “CXC”; the second subgroup is referred to as “CC”; the third chemokine subgroup is referred to as “CX3C”; and the fourth chemokine subgroup is referred to as “C”. Within these subgroups, the chemokines are further divided into related families that are based upon amino acid sequence homology. The CXC chemokine families include the IP-10 and Mig family; the GROα, GROβ, and GROβ family; the interleukin-8 (IL-8) family; and the PF4 family. The CC chemokine families include the monocyte chemoattractant protein (MCP) family; the family including macrophage inhibitory protein-1α (MIP-1α), macrophage inhibitory protein-1 β (MIP-1 β), and regulated on activation normal T cell expressed (RANTES). The stromal cell-derived factor 1α (SDF-1α) and stromal cell-derived factor 1β (SDF-1β) represent a chemokine family that is approximately equally related by amino acid sequence homology to the CXC and CC chemokine subgroups. The CX3C chemokine family includes fractalkine; The C chemokine family includes lymphotactin. In general, the CXC chemokines are bound by members of the CXCR class of receptors; the CC chemokines are bound by the CCR class of receptors; the CX3C chemokines are bound by the CX3CR class of receptors; and the C chemokines are bound by the CR class of receptors.
Cells which express chemokine receptors include migratory cells such as lymphocytes, granulocytes, and antigen-presenting cells (APCs) that are believed to participate in immune responses or that may release other factors to mediate other cellular processes in vivo. The presence of a chemokine gradient serves to attract migratory cells which express the chemokine receptors. For example, migratory cells can be attracted by a chemokine gradient to a particular site of inflammation, at which location they play a role in further modifying the immune response. Chemokine receptors also are involved in interacting with viral proteins. In particular, CXCR4(fusin), CCR5, and other chemokine receptors have been identified as co-receptors for HIV-1 and HIV-2. In addition, chemokine receptors are expressed on a variety of non-motile cells such as neurons, microglia, epithelial cells and fibroblasts. Chemokines are also known to affect a variety of non-migratory cell functions such as granule release, cytokine release, angiogenesis, growth and differentiation. However, the half-life for chemokines in vivo is relatively short. (See, e.g., D. Hechtman, et al., J. Immunol. 147(3): 883-892 (1991) which reports a decline to preinjection levels of IL-8 in 30 minutes).
Various approaches also have been tried to extend the half-life of injected chemokines in vivo, as well as to accomplish the targeted delivery of chemokines to cell populations to establish a chemokine gradient. For example, International Application No. PCT/US98/04002, (Publication No. WO 98/38212, inventors S. Herrmann and S. Swanberg), entitled “Chimeric Polypeptides Containing Chemokine Domains,” reports a chimeric DNA molecule comprising a sequence encoding a chemokine polypeptide covalently attached to a heterologous polypeptide such as the binding domain of an antibody. Similarly, International Application No. PCT/US98/01785, (Publication No. WO 98/33914, inventors J. Rosenblatt, et al.,), entitled “Chimeric Antibody Fusion Proteins for the Recruitment and Stimulation of an Antitumor Immune Response,” reports chimeric molecules which include a binding region which specifically binds to a tumor-specific antigen and a chemokine and/or co-stimulatory ligand. U.S. Pat. No. 5,645,835, issued to H. Fell, Jr. and M. Gayle, entitled “Therapeutic Antibody based Fusion Proteins,” also reports an antibody-based fusion protein which includes an immunoglobulin portion coupled to a biologically active lymphokine. Unfortunately, each of the foregoing methods requires the creation of a chemokine fusion protein, thereby necessitating the development of tailored methods for the generation of each different chemokine construct. Thus, despite the innovations advocated in connection with fusion protein technology, there exists no universal approach for the targeted delivery of chemokines to cells which express the cognate chemokine receptor. Accordingly, a need still exists for a generally applicable method of chemokine delivery to cells in vivo or in vitro. Preferably, the universal method would be one which is easily reversible in vivo or in vitro.